Drug delivery system

ABSTRACT

A drug delivery system for the controlled release of a pharmaceutically-active compound by oral route comprises an intercalate of a layered double hydroxide having, before intercalation, layers of metal hydroxides, and having intercalated therein a pharmaceutically-active compound having at least one anionic group. A preferred layered double hydroxide is one that has layers which comprise [LiAl 2 (OH) 6 ] + . The drug delivery system has use in the delivery of drugs such as 4-biphenylacetic acid, Diclofenac, Gemfibrozil, Ibuprofen, Naproxen, 2-Propylpentanoic acid and Tolfenamic acid.

The present invention relates to a drug delivery system. Moreparticularly, it relates to a system in which a drug is intercalatedinto a layered double hydroxide.

Layered double hydroxides (LDHs) are a class of compounds which comprisetwo metal cations and have a layered structure. A brief review of LDHsis provided in Chemistry in Britain, September 1997, pages 59 to 62. Thehydrotalcites, perhaps the most well-known examples of LDHs, have beenstudied for many years.

LDHs can be represented by the general formula [M^(II) _((1-x))M^(III)_(x)(OH)₂]^(x+)A^(z−) _(x/z).yH₂O or [M^(I) _((1-x))M^(II)_(x)(OH)₂]^(n+)A^(z−) _(n/z).yH₂O, where M^(I), M^(II) and M^(III) aremono, di- and trivalent metal cations respectively, that occupyoctahedral positions in hydroxide layers, A^(z−) is an interlayercharge-compensating anion where z is an integer, such as CO₃ ²⁻, NO₃ ⁻or Cl⁻, n=2x−1, x is a number less than 1 and y is 0 or a number greaterthan 0. A large number of LDHs with a wide variety of M^(II)-M^(III)cation pairs (e.g., Ca—Al) as well as the M^(I)-M^(III) cation pair(Li—Al) with different anions in the interlayer space have been reportedand studied.

It is known that certain organic species may be intercalated into thelayers in some LDHs and into clays. For example, Ogawa et al., inChemistry Letters, 1992, no. 3, p. 365-368, describe the intercalationof maleic and methylmaleic acids into the clay montmorillonite in asolid state reaction. The geometrical isomers of the acids, fumaric andmethylfumaric acids, were not intercalated in the solid state reaction.However, when an ethanolic solution of the two isomers was used, themontmorillonite showed no selectivity and both isomers wereintercalated.

The structure of the layered materials [LiAl₂(OH)₆]X, where X is Cl, Bror NO₃, and their hydrates has been described by Besserguenev et al., inChem. Mater, 1997, no. 9, p. 241-247. The materials can be produced bythe reaction of gibbsite [γ-Al(OH)₃] or other forms of Al(OH)₃, such asbayerite, nordstrandite or doyleite, with lithium salts of formula LiX.The materials can also be formed in other ways, such as by directprecipitation (see, for example, Serna et al., Clays & Clay Minerals,(1997), 25,384). The structure of the LiAl₂(OH)₆ ⁺ layers in thecompounds is unusual amongst LDHs since it is based on an orderedarrangement of metal cations within the layers.

The synthesis of LiAl₂(OH)₆ ⁺ compounds is described in U.S. Pat. No.4,348,295 and U.S. Pat. No. 4,348,297. The use of the materials forseparating hydrocarbons and for gas chromatograph columns is taught inU.S. Pat. No. 4,430,097 and U.S. Pat. No. 4,321,065, respectively. Inboth of these latter two documents, the technology described does notinvolve intercalation chemistry but surface interactions with thestationary phase i.e., liquid-solid or gas-solid interactions.

Intercalates of compounds of formula LiOH.2Al(OH)₃ are described in U.S.Pat. No. 4,727,167 and U.S. Pat. No. 4,812,245. Both documents relate touses of the intercalates as additives to organic materials such asmineral oils.

A few other LDHs having cation ordering are known. The layered doublehydroxide [Ca₂Al(OH)₆]₂ ⁺SO₄ ²⁻ is an example.

LDHs exhibit a wide range of anion-exchange reactions with guests suchas organic carboxylates, sulfonates and a range of anionic metalcomplexes. These materials are of significant technological importancein diverse areas such as catalysis, optics, medical science andseparation science.

The application of LDHs in separation science has until recently beenlargely restricted to their role as fast, efficient, high capacityion-exchange materials. The major application being the removal oforganic and inorganic anions from aqueous streams. According to WO99/24139 a compound comprising at least two negatively charged groupsconnected by a linker group can be separated from a mixture containingit by selectively intercalating it into an LDH. For example, it wasdisclosed therein that when [LiAl₂(OH)₆]Cl.H₂O is treated with anequimolar mixture of the disodium salts of either the 1,2-, 1,3- or1,4-dibenzoic acids then the only crystalline phase observed is formedby preferential and exclusive intercalation of the 1,4-dibenzoateanions.

Choy et al., J. Am. Chem. Soc. 1999, 121, 1399-1400, have reported thatthe nucleoside monophosphates such as adenosine-5′-monophosphate (AMP),guanosine-5′-monophosphate (GMP) and cytidine-5′-monophosphate (CMP) canbe ion-exchange intercalated in the layered double hydroxide[Mg_(0.68)Al_(0.32)(OH)₂](NO₃)_(0.32).1.2H₂O.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides release profiles for diclofenac at pH 4 and pH 7 from adelivery system according to an embodiment of the invention.

FIG. 2 provides release profiles for naproxen at pH 4 and pH 7 from adelivery system according to an embodiment of the invention.

FIG. 3 provides release profiles for gemfibrozil at pH 4 and pH 7 from adelivery system according to an embodiment of the invention.

FIG. 4 provides release profiles for tolfenamic at pH 4 and pH 7 from adelivery system according to an embodiment of the invention.

FIG. 5 provides release profiles for 4-biphenylacetic acid at pH 4 andpH 7 from a delivery system according to an embodiment of the invention.

FIG. 6 provides a release profile for naproxen at pH 7 from a deliverysystem according to any embodiment of the invention.

The present invention provides a drug delivery system comprising anintercalate of a layered double hydroxide having, before intercalation,layers of metal hydroxides and having intercalated therein apharmaceutically-active compound having at least one anionic group.

The present invention is based on the discovery that apharmaceutically-active compound having at least one anionic group canbe intercalated into an LDH compound and that the intercalate releasesthe pharmaceutically-active compound in a controlled manner whensubjected to pH conditions that may prevail inside the stomach of apatient. It is known that certain pharmaceutically-active compounds,when administered orally, may cause irritation of the stomach. Somepatients are, of course, more vulnerable to irritation of this kind thanothers. By controlling the release of such compounds in the stomach sucha side-effect can be avoided or, at least, reduced.

The layered double hydroxide that can be used in the drug deliverysystem of the invention comprises two metal cations and hydroxide ionsand has a layered structure. Between the layers, the LDH contains anintercalated anionic group which is one that can be displaced by thepharmaceutically-active compound.

A first, preferred, class of LDH compounds that can be used in themanufacture of the drug delivery system of the invention has the generalformula I[M^(I)M₂ ^(III)(OH)₆]⁺[A_(1/n) ^(n−)]  (I)in which M^(I) is a monovalent metal cation, M^(III) is a trivalentmetal cation, A is a displaceable anion and n is an integer. Thesecompounds are optionally, but preferably, hydrated. The amount of waterof hydration may be a stoichiometric amount or a non-stoichiometricamount. Of this class of LDH compounds, those wherein M^(I) is a lithiumion and M^(III) is an aluminium ion are particularly preferred such thatthe layers in the compound comprise [LiAl₂(OH)₆]⁺. The cations in such alayer have an ordered arrangement, i.e., the LDH has cation ordering.The ordered (i.e., non-random) arrangement of cations is believed to bebeneficial and to enhance the intercalation of thepharmaceutically-active compound in the system of the invention.

In the above formula I the anion A is one that can be displaced from itslocation between the metal cation-containing layers in the LDH by thepharmaceutically-active compound. For example, it may be an anionselected from hydroxide, halide (i.e., fluoride, chloride, bromide oriodide), sulfate or nitrate ions. Preferably, the anion A is chloride ornitrate.

A second, preferred, class of LDH compound that can be used in themanufacture of the drug delivery system of the invention has the generalformula II[M_((1-x)) ^(II)M_(x) ^(III)(OH)₂]^(x+)[A_(x/n) ^(n−)]  (II)in which M^(II) is a divalent metal cation, for example, Ca²⁺, Mg²⁺,Zn²⁺ and Ni²⁺ ions, M^(III) is a trivalent metal cation, for exampleAl³⁺ and Fe³⁺ ions, A is a displaceable anionic group such as onedisclosed above in connection with the described first class of LDHcompounds, n is an integer and x is a number less than 1. Such compoundsare optionally, but preferably, hydrated. The water of hydration, ifpresent, may be present in a stoichiometric amount or anon-stoichiometric amount.

A preferred LDH compound for use in preparing the drug delivery systemof the invention is [LiAl₂(OH)₆]Cl.H₂O.

The drug delivery system of the invention comprises an LDH in which isintercalated a pharmaceutically-active compound having at least oneanionic group. The pharmaceutically-active compound may be any compoundwhich may have use in the treatment of any disease, disorder orcondition in the body of an animal, including human, provided that thecompound has activity when administered by an oral route and providedthat it has at least one anionic group which will enable it tointercalate into the LDH to displace the anion A from the initial LDHcompound. Thus, provided that the above requirements are met thepharmaceutically-active compound may be a drug, a pro-drug or drugprecursor or a substance for treating a treatable disorder or conditionof the animal body, including the human body. Such active compounds haveat least one anionic group, for example a carboxylic acid group or anon-toxic metal or ammonium salt thereof. Examples ofpharmaceutically-active compounds that may be intercalated into an LDHto form an intercalation compound having use as a drug delivery systemaccording to the invention include, but are not limited to,4-biphenylacetic acid, sodium (2-(2,6-dichloroanilino)phenyl)acetate(Diclofenac Sodium), 2,2-dimethyl-5-(2,5-xylyloxy)valeric acid(Gemfibrozil), 2-(4-isobutylphenyl)propionic acid (Ibuprofen),(+)-2-(6-methoxy-2-naphthyl)propionic acid (Naproxen), 2-propylpentanoicacid and N-(3-chloro-o-tolyl)anthranilic acid (Tolfenamic acid).

In order to effect intercalation, an aqueous solution of thepharmaceutically-active compound, optionally in the form of a non-toxicsalt thereof, is treated with the layered double hydroxide and then theintercalate compound, so formed, is separated from the reaction mixture.Typically, the treatment will be performed by, firstly, preparing anaqueous suspension of the LDH compound and then mixing this with anaqueous solution of the pharmaceutically-active compound (or a non-toxicsalt thereof. Preferably, an aqueous suspension of the LDH is treated byultrasonication for a period of time of from 1 to 60 minutes, morepreferably from 30 to 45 minutes, prior to mixing this with the solutioncontaining the pharmaceutically-active compound, since this priorsonication treatment enhances the extent of the intercalation reaction.Typically, the intercalation reaction is carried out by stirring theaqueous mixture of the reactants for a period of time within the rangeof from 2 to 72 hours. The pharmaceutically-active compound in thesolution treated with the LDH will preferably be in a molar excess withrespect to the LDH. Typically, the molar ratio ofpharmaceutically-active compound to LDH will be at least 2:1 since suchguest:host ratios promote a greater extent of intercalation. Thetemperature of the reaction mixture will typically be held at least 30°C. for at least part of the reaction period. Whereas Naproxen isintercalated into the LDH after a reaction time of 1 to 2 days at 30°C., the reaction of Tolfenamic acid with the LDH requires a longerperiod of time and a higher reaction temperature, typically about 3 daysat a temperature of about 80° C.

After the intercalation reaction, the particles of the LDH containingintercalated pharmaceutically-active compound are separated from theaqueous medium, for instance by filtration.

The separated LDH particles containing the intercalatedpharmaceutically-active compound will then be dried prior to formulationinto the required oral dosage units.

The intercalate compounds have been found to release thepharmaceutically-active compound in a controlled manner when subjectedto an acid environment similar to that which exists in the stomach of ananimal (including a human). This is because the LDH is broken down bytreatment with a dilute acid, such as hydrochloric acid. LDH compounds,themselves, are known to have an antacid effect. Thus, an intercalate ofthe invention when administered orally to a patient has the effect ofaltering the pH of the environment inside the stomach of the patientwhich, in turn, affects the breakdown of the intercalate and, therefore,the rate of release of the pharmaceutically-active compound from theintercalate. Since the rate of breakdown of the intercalate in thestomach and the degree of antacid effect depends on the chemical natureof the lattice of the LDH used it is possible to control or modify therate of release of the pharmaceutically-active compound from theintercalate by an appropriate selection of the host lattice used in themanufacture of the intercalate. The pH of the contents of the stomachcan also be controlled by the addition of a buffer, for instance, aphosphate buffer. Thus, the incorporation of a buffer into aformulation, which includes the intercalate containing thepharmaceutically-active compound, to be administered to a patient allowsthe pH to be fine tuned to optimise the rate of breakdown of the LDHlattice and, thus, the rate of release of the pharmaceutically-activecompound from the intercalate. According to a different embodiment, itmay be advantageous to include, with the intercalate compound in theformulation to be administered to a patient, a non-toxic compound whichcontains an anion that intercalates between the layers in the LDH inpreference to the pharmaceutically-active compound. By providing such acompound, the release of the pharmaceutically-active compound in thepatient's stomach is promoted by the action of the anion to displace thepharmaceutically-active compound from the layers in the LDH. Suitableanions for this purpose include carbonate and hydrogen carbonate anionsalthough anions, which intercalate more or less strongly than carbonatecan be used. A carbonate compound is, however, preferred on account ofthe strong capacity of carbonate anion to bind with the LDH and displacethe guest pharmaceutically-active compound from the LDH. Examples ofsuitable non-toxic carbonate and hydrogen carbonate compounds that canbe used in this embodiment of the invention include CaCO₃, Ca(HCO₃)₂,MgCO₃ and Mg(HCO₃)₂.

EXAMPLES Example 1 Intercalation of Pharmaceutically-Active Compounds in[LiAl₂(OH)₆]Cl.H₂O

Table 1 lists pharmaceutically-active compounds which we haveintercalated into a layered double hydroxide (LDH) host of formula[LiAl₂(OH)₆]Cl.H₂O. The intercalation of the drug was achieved by adding1.4 mmol of the sodium salt of the drug in 10 ml of deionised H₂O to asuspension of 0.7 mmol of the host in 10 ml of deionised H₂O. Thesuspension of the host was sonicated for 30 minutes prior to theaddition of the sodium salt of the drug. The mixture was then stirred ina sealed glass ampoule for 1-2 days at a temperature of 30° C.

4-Biphenylacetic acid and Tolfenamic acid are anti-inflammatory andanalgesic agents. Diclofenac is used for the treatment of arthritis,ibuprofen and naproxen are both non-steroidal anti-inflammatory agents.Gemfibrozil is a lipid regulating agent and 2-propylpentanoic acidinhibits GABA transaminase.

TABLE 1 Summary of the guest molecule used and the analytical andstructural data of the LDH-drug intercalation compounds. InterlayerElemental Spacing/ Analysis Guest Molecular Structure of Guest^(a) Å^(b)Found (calc)^(c) 4-Biphenylacetic acid C₁₄H₁₂O₂

20.4 C 30.77 (30.77) H 5.16 (5.20) x = 0.58, y = 2 DiclofenacC₁₄H₁₀Cl₂NaNO₂

22.3 C 30.91 (30.92) H 4.12 (3.91) N 2.60 (2.58) x = 0.72. y = 1.Gemfibrozil C₁₅H₂₂O₃

23.2 C 35.35 (35.36) H 6.56 (6.65) x = 0.69, y = 1 Ibuprofen C₁₃H₁₈O₂

22.7 C 31.92 (31.98) H 6.15 (5.99) x = 0.75. y = 3 Naproxen C₁₄H₁₄O₃

21.5 C 27.91 (28.08) H 4.98 (4.99) x = 0.48. y = 1 2-Propylpentanoicacid C₈H₁₆O₂

18.7 C 14.78 (14.82) H 5.77 (6.04) x = 0.35, y = 1 Tolfenamic acidC₁₄H₁₂ClNO₂

21.9 C 23.24 (23.18) H 5.25 (5.29) N 1.90 (1.93) x = 0.46. y = 3^(a)Neutral guest molecules were converted to the sodium salt prior tointercalation. ^(b)Based on hexagonal cell α = β = 90°, γ = 120°, a = b= 5.1Å, and c = 2 × d₍₀₀₂₎ ^(c)Based on the general formula formulaLi_(x)Al₂(OH)₆[drug]_(x′)yH2OMethods of Recovery/Release of the Drugs from the Solid Host.

All of the above drugs have been quantitatively exchanged back out ofthe host LDH, for example, by using one of the following procedures:

-   -   1. Addition of carbonate; adding 0.113 g of Na₂CO₃ to approx.        0.100 g of the intercalation compound in 8 ml of D₂O and        stirring overnight in a sealed glass ampoule.    -   2. Addition of acid; All the intercalation compounds react with        0.2M HCl to produce the neutral drug molecule.    -   3. Addition of phosphate buffer (ca. pH7).

NMR spectra and XRD patterns were measured to confirm the release of thedrugs.

Example 2

Intercalation compounds were obtained by intercalating thepharmaceutically-active compounds described in Example 1 into[LiAl₂(OH)₆]Cl.H₂O according to the procedure of Example 1.

Release of the drugs from their intercalation compounds was performed ineach case by the addition of 0.0250 g-0.100 g of the intercalationcompound to 250 mL phosphate buffer solution at 37° C. (bodytemperature) in a round bottom flask and the mixture stirred at 1000rpm. The release in phosphate buffer at pH 7 and at pH 4 wasinvestigated. Aliquots were removed from the flask at regular timeintervals, the solution was filtered and the UV spectrum of the filtraterecorded in a 1 cm² quartz cuvette. A baseline scan using the neatsolution was recorded prior to the collection of the first spectrum ofthe filtrate.

The release profiles for diclofenac at pH 4 and pH 7 are shown inFIG. 1. The release profiles for Naproxen at pH 4 and pH 7 are shown inFIG. 2. The release profiles for Gemfibrozil at pH 4 and pH 7 are shownin FIG. 3. The release profiles for Tolfenamic acid at pH 4 and pH 7 areshown in FIG. 4. The release profiles for 4-biphenylacetic acid at pH 4and pH 7 are shown in FIG. 5.

The release of Diclofenac (FIG. 1), Naproxen (FIG. 2) and4-biphenylacetic acid (FIG. 5) was rapid at pH 4 but was slower and morecontrolled at pH 7.

Example 3 Intercalation of Pharmaceutically-Active Compounds in[Ca₂Al(OH)₆]NO₃.xH₂O

Intercalation of the pharmaceutically-active compounds was achieved bythe addition of 1.4 mmol of the sodium salt of the drug in 10 mldeionised H₂O to 0.7 mmol of the LDH host of formula[Ca₂Al(OH)₆]NO₃.xH₂O. The mixture was then stirred in a sealed glassampoule for 18 hours at a temperature of 80° C. The solid products wereisolated by filtration and washed with an excess of deionised water andacetone and allowed to dry in air. The formulae and d-spacings of theintercalation compounds synthesised are listed in the following Table 2.

TABLE 2 Drug Molecule Intercalation Compound d-spacing Å4-Biphenylacetic acid [Ca_(1.875)Al(OH)₆][C₁₄H₁₁O₂]_(0.75)•2H₂O 19.5C₁₄H₁₂O₂ Diclofenac [Ca_(1.9)Al(OH)₆][C₁₄H₁₀Cl₂NO₂]_(0.8)•2H₂O 22.4C₁₄H₁₀Cl₂NaNO₂ Gemfibrozil [Ca_(1.825)Al(OH)₆][C₁₅H₂₁O₃]_(0.65)•H₂O 22.5C₁₅H₂₂O₃ Ibuprofen [Ca_(1.9)Al(OH)₆][C₁₃H₁₇O₂]_(0.8)•H₂O 19.8 C₁₃H₁₈O₂Naproxen [Ca₂Al(OH)₆][C₁₄H₁₃O₃]_(0.63)•3H₂O 19.7 C₁₄H₁₄O₃ Tolfenamicacid [Ca_(1.75)Al(OH)₆][C₁₄H₁₁ClNO₂]_(0.5)•2H₂O* 19.8 C₁₄H₁₂ClNO₂ *Inorder to achieve the intercalation of tolfenamic acid the mixture washeated at a temperature of 80° C. for approx. 3 days.

Release of Naproxen was performed and investigated as described inExample 2. The release profile of Naproxen from its intercalationcompound at pH 7 is shown in FIG. 6.

Example 4 Intercalation of Pharmaceutically-Active Compounds in[Mg₂Al(OH)₆]NO₃.H₂O

Intercalation of the drug molecules listed in Table 2 was achieved bythe addition of 1.4 mmol of the sodium salt of the drug in 10 mldeionised H₂O to 0.7 mmol of the LDH host of formula[Mg₂Al(OH)₆]NO₃—H₂O. The mixture was then stirred in a sealed glassampoule for 12 hours at a temperature of 60° C. The solid products wereisolated by filtration and washed with an excess of deionised water andacetone and allowed to dry in air.

The invention claimed is:
 1. A drug delivery system comprising anintercalate of a layered double hydroxide having, before intercalation,layers of metal hydroxides, and having intercalated therein apharmaceutically-active compound having at least one anionic group,wherein said intercalate is present in an oral dosage formulation, andwhich additionally comprises a non-toxic compound having an anion whichis capable of displacing the pharmaceutically-active compound from theintercalate, wherein the non-toxic compound is selected from magnesiumcarbonate, magnesium hydrogen carbonate, calcium carbonate and calciumhydrogen carbonate.
 2. The system according to claim 1, wherein thelayered double hydroxide, before intercalation, is represented by thegeneral formula[M^(II) _((1-x))M^(III) _(x)(OH)₂]^(x+)[A^(n−) _(.x/n)] in which M^(II)is a divalent metal cation; M^(III) a trivalent metal cation; A is adisplaceable anion; n is an integer; and x is a positive number lessthan 1, which compound is optionally hydrated with a stoichiometricamount or a non-stoichiometric amount of water.
 3. The system accordingto claim 2, wherein M^(II) is Mg or Ca and M^(III) is Al.
 4. The systemaccording to claim 2, wherein A is selected from OH, F, CI, Br, I, SO₄,and NO₃.
 5. The system according to claim 2, wherein the layered doublehydroxide, before intercalation, is represented by the general formula[M^(I)M^(III) ₂(OH)₆]⁺[A^(n−) _(1/n)] in which M^(I) is a monovalentmetal cation; M^(III) a trivalent metal cation; A is a displaceableanion; and n is an integer, which compound is optionally hydrated with astoichiometric or non-stoichiometric amount of water.
 6. The systemaccording to claim 5, wherein M^(I) is Li and M^(III) is Al.
 7. Thesystem according to claim 5, wherein A is selected from OH, F, Cl, Br,I, SO₄, and NO₃.
 8. The system according to claim 7, wherein the layereddouble hydroxide is [LiAl₂(OH)₆]Cl.H₂O.
 9. The system according to claim1, wherein the pharmaceutically-active compound having at least oneanionic group is a pharmaceutically-active compound containing at leastone carboxylic acid group or a non-toxic salt thereof.
 10. The systemaccording to claim 1, wherein the pharmaceutically-active compound isselected from 4-biphenylacetic acid, Diclofenac, Gemfibrozil, Ibuprofen,Naproxen, 2-propylpentanoic acid and Tolfenamic acid.
 11. The systemaccording to claim 1, wherein the intercalate of a layered doublehydroxide having, intercalated therein, a pharmaceutically-activecompound having at least one anionic group is made by a method whichcomprises: treating an aqueous solution of the pharmaceutically-activecompound, optionally in the form of a non-toxic salt thereof, with thelayered double hydroxide; separating the intercalate of the layereddouble hydroxide.
 12. The system according to claim 1, furthercomprising a buffer.
 13. The system according to claim 12, wherein thebuffer is a phosphate buffer.
 14. A drug delivery system comprising: anintercalate of a layered double hydroxide having, before intercalation,layers of metal hydroxides, and having intercalated therein apharmaceutically-active compound having at least one anionic group,wherein said intercalate is in the form of particles present in an oraldosage formulation; and a non-toxic compound having an anion which iscapable of displacing the pharmaceutically-active compound from theintercalate, wherein the non-toxic compound is selected from magnesiumcarbonate, magnesium hydrogen carbonate, calcium carbonate and calciumhydrogen carbonate.